The goal of this proposal is to explore the transgenerational epigenetic inheritance of longevity. A fundamental question is whether epigenetic changes that affect lifespan in the parental generation can still impact the lifespan of the subsequent generations even when the factors that led to these changes are no longer present. While some evidence of transgenerational epigenetic inheritance for simple traits exist, very little is known about the transgenerational inheritance of acquired complex traits. Understanding the epigenetic memory of longevity between generations has the potential to revolutionize the current paradigm on the inheritance of complex diseases and will also have a broad impact on our understanding of epigenome reprogramming. We recently made the surprising discovery that mutations in specific regulators of trimethylated lysine 4 on histone H3 (H3K4me3) in parents lead to lifespan extension in descendants for up to three generations, even after the initial mutation is no longer present. This unexpected discovery has led our lab in a new direction. The questions we ask are: what are the mechanisms underlying transgenerational epigenetic inheritance of longevity? Is epigenetic memory of lifespan generalizable to vertebrates? Could environmental factors that affect aging, such as dietary intake, impact subsequent generations even when the environment is back to normal? Could this unconventional mode of inheritance have the evolutionary advantage of ?informing? future generations about the ancestors? environment? We will develop an innovative and exciting framework to address transgenerational inheritance of longevity experimentally. A major goal will be to systematically identify the molecules that are inherited in a transgenerational manner and that mediate this epigenetic memory by combining unbiased genomics, proteomics and metabolomics technologies and single-cell approaches. Another challenge will be to examine the importance of epigenetic memory of aging and longevity in other species. Our ability to use complementary model organisms, including the worm C. elegans, the short-lived African killifish N. furzeri, and longer-lived mammalian mouse models, will be particularly helpful for these studies. We believe that these studies will have a transformative impact on our way of approaching the etiology of complex diseases, including diabetes, cancer, and neurodegenerative disorders, and in developing new modes of prevention and treatments for these diseases. Our studies will also have broad and fundamental implications on the basic biology of epigenome reprogramming and maintenance, which is a crucial step in developing and improving stem cell therapies and in vitro fertilization. Project Description